Seoul National University Cancer Research Institute, South Korea.
Seoul National University Cancer Research Institute, South Korea; Department of Internal Medicine, Seoul National University Hospital, South Korea.
Cancer Lett. 2020 Dec 28;495:135-144. doi: 10.1016/j.canlet.2020.09.018. Epub 2020 Sep 23.
NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si)RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.
NRAS 突变在非小细胞肺癌（NSCLC）患者中很少见，目前也没有针对 NRAS 突变型 NSCLC 的批准治疗方法。在这里，我们评估了泛 RAF 抑制剂对人类 NRAS 突变型 NSCLC 细胞系的影响，并使用人类激酶组小干扰（si）RNA 或 CRISPR/Cas9 文库进行高通量筛选，以确定联合 NSCLC 治疗的新靶点。我们的结果表明，人类 NRAS 突变型 NSCLC 细胞对泛 RAF 抑制剂具有中等敏感性。高通量激酶组筛选进一步表明，G2/M 期阻滞，特别是在敲低 Polo 样激酶 1（PLK1）后，可抑制人类 NRAS 突变型 NSCLC 细胞以及用 II 型泛 RAF 抑制剂 LXH254 治疗的细胞的生长。此外，用 volasertib 加 LXH254 治疗，即双重阻断 PLK1 和泛 RAF，与 LXH254 单药治疗相比，对抑制长期细胞活力更有效，这表明这种联合治疗策略可能在临床上产生有前景的结果。
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